As the DNA sequences of the human genome are revealed, it is increasingly clear that many genes are polymorphic. In coding or noncoding regions of a specific gene, there may be either a single base pair substitution of one nucleotide for another, multiple base pair changes, or a variable number of repeats of a short, repetitive DNA sequence.
Polymorphic variations may influence the rate of gene transcription, the stability of the messenger RNA, or the quantity and activity of the resulting protein. Thus, the susceptibility or severity of a number of disorders or conditions may be influenced by possession of specific alleles of polymorphic genes.
An example of a polymorphic gene is the gene for mannose-binding lectin. Mannose-binding lectin (MBL) is a circulating protein, and a component of the innate immune defense system. The lectin binds to mannose, N-acetylglucosamine and fucose residues on the surface of microorganisms. Such binding results in complement activation.
In addition, macrophages and dendritic cells contain cell surface receptors that recognize MBL, facilitating opsonization of microorganisms with bound MBL on their surface (Babovic-Vuksanovic et al.,Asthma Immunol., 1999; 82:134-43). Reduction in serum levels of MBL have been associated with opsonization defects (Super et al., Lancet, 1989; 2:1236-1239) and with an increased risk of recurrent infections in young children (Turner et al., Clin. Exp. Immunol., 1991; 86:53-56 and Koch et al., JAMA, 2001; 285:1316-1321).
At least three alleles exist for the mannose-binding lectin gene. The wild type allele is called allele A. Genetic variants of the wild type allele are considered to be mutant alleles.
An example of a mutant allele of mannose-binding lectin is allele B, which is the most studied of the mutant alleles. In allele B, there is a single nucleotide substitution of an adenine for a guanine in codon 54 of exon 1. This substitution results in replacement of aspartic acid for glycine in the MBL protein. As a consequence of this alteration, the assembly of the mature MBL protein, including, for example, glycosylation, is inhibited, and its stability is markedly reduced (Sumiya et al., Lancet, 1991; 337:1569-1570 and Lipscombe et al., Immunology, 1995; 85:660-667).
The decrease in circulating MBL concentrations has been shown to correlate with possession of mutant alleles in exon 1 of MBL. Serum levels of MBL are approximately 1.2 to 1.7 μg/ml in individuals who are homozygous for allele A, 0.3 μg/ml in individuals who are heterozygous for allele A and B, and 10 ng/ml in individuals homozygous for allele B.
Vulvovaginal candidiasis is a yeast infection of the vulva and vagina. Millions of women worldwide suffer from vulvovaginal candidiasis. Women with recurrent vulvovaginal candidiasis experience frequent episodes of infection, which result in considerable morbidity and suffering.
Vulvar vestibulitis is a condition characterized by redness and pain of the vaginal vestibule and an inability to experience pain-free vaginal penetration. There is currently no known cause for vulvar vestibulitis. Many women with vulvar vestibulitis syndrome suffer physically and emotionally for months or years. These women typically see a number of physicians, and try many unsuccessful treatments in search of relief.
Several environmental factors have been identified which predispose women to recurrent vulvovaginal candidiasis or vulvar vestibulitis syndrome. These factors include pregnancy, oral contraceptives, exogenous hormones, antibiotics, diabetes mellitus, etc. However, the majority of women with recurrent vulvovaginal candidiasis or vulvar vestibulitis syndrome are not subjected to these predisposing factors.
Therefore, it would be beneficial to be able to identify females who are at risk for developing vulvovaginal candidiasis or vulvar vestibulitis syndrome. It would also be beneficial to be able to treat and/or prevent vulvovaginal candidiasis or vulvar vestibulitis syndrome.